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Mol Cell Biol. Sep 1994; 14(9): 6153–6163.
PMCID: PMC359142

Displacement of an E-box-binding repressor by basic helix-loop-helix proteins: implications for B-cell specificity of the immunoglobulin heavy-chain enhancer.


The activity of the immunoglobulin heavy-chain (IgH) enhancer is restricted to B cells, although it binds both B-cell-restricted and ubiquitous transcription factors. Activation of the enhancer in non-B cells upon overexpression of the basic helix-loop-helix (bHLH) protein E2A appears to be mediated not only by the binding of E2A to its cognate E box but also by the resulting displacement of a repressor from that same site. We have identified a "two-handed" zinc finger protein, denoted ZEB, the DNA-binding specificity of which mimics that of the cellular repressor. By employing a derivative E box that binds ZEB but not E2A, we have shown that the repressor is active in B cells and the IgH enhancer is silenced in the absence of binding competition by bHLH proteins. Hence, we propose that a necessary prerequisite of enhancer activity is the B-cell-specific displacement of a ZEB-like repressor by bHLH proteins.

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  • Aronheim A, Ohlsson H, Park CW, Edlund T, Walker MD. Distribution and characterization of helix-loop-helix enhancer-binding proteins from pancreatic beta cells and lymphocytes. Nucleic Acids Res. 1991 Jul 25;19(14):3893–3899. [PMC free article] [PubMed]
  • Bain G, Gruenwald S, Murre C. E2A and E2-2 are subunits of B-cell-specific E2-box DNA-binding proteins. Mol Cell Biol. 1993 Jun;13(6):3522–3529. [PMC free article] [PubMed]
  • Beckmann H, Su LK, Kadesch T. TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. Genes Dev. 1990 Feb;4(2):167–179. [PubMed]
  • Buskin JN, Hauschka SD. Identification of a myocyte nuclear factor that binds to the muscle-specific enhancer of the mouse muscle creatine kinase gene. Mol Cell Biol. 1989 Jun;9(6):2627–2640. [PMC free article] [PubMed]
  • Carr CS, Sharp PA. A helix-loop-helix protein related to the immunoglobulin E box-binding proteins. Mol Cell Biol. 1990 Aug;10(8):4384–4388. [PMC free article] [PubMed]
  • Clerc RG, Corcoran LM, LeBowitz JH, Baltimore D, Sharp PA. The B-cell-specific Oct-2 protein contains POU box- and homeo box-type domains. Genes Dev. 1988 Dec;2(12A):1570–1581. [PubMed]
  • Davis RL, Cheng PF, Lassar AB, Weintraub H. The MyoD DNA binding domain contains a recognition code for muscle-specific gene activation. Cell. 1990 Mar 9;60(5):733–746. [PubMed]
  • Gregor PD, Sawadogo M, Roeder RG. The adenovirus major late transcription factor USF is a member of the helix-loop-helix group of regulatory proteins and binds to DNA as a dimer. Genes Dev. 1990 Oct;4(10):1730–1740. [PubMed]
  • Guan KL, Dixon JE. Eukaryotic proteins expressed in Escherichia coli: an improved thrombin cleavage and purification procedure of fusion proteins with glutathione S-transferase. Anal Biochem. 1991 Feb 1;192(2):262–267. [PubMed]
  • Henthorn P, Kiledjian M, Kadesch T. Two distinct transcription factors that bind the immunoglobulin enhancer microE5/kappa 2 motif. Science. 1990 Jan 26;247(4941):467–470. [PubMed]
  • Henthorn PS, Raducha M, Edwards YH, Weiss MJ, Slaughter C, Lafferty MA, Harris H. Nucleotide and amino acid sequences of human intestinal alkaline phosphatase: close homology to placental alkaline phosphatase. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1234–1238. [PMC free article] [PubMed]
  • Hu JS, Olson EN, Kingston RE. HEB, a helix-loop-helix protein related to E2A and ITF2 that can modulate the DNA-binding ability of myogenic regulatory factors. Mol Cell Biol. 1992 Mar;12(3):1031–1042. [PMC free article] [PubMed]
  • Hu YF, Lüscher B, Admon A, Mermod N, Tjian R. Transcription factor AP-4 contains multiple dimerization domains that regulate dimer specificity. Genes Dev. 1990 Oct;4(10):1741–1752. [PubMed]
  • Jacobs Y, Vierra C, Nelson C. E2A expression, nuclear localization, and in vivo formation of DNA- and non-DNA-binding species during B-cell development. Mol Cell Biol. 1993 Dec;13(12):7321–7333. [PMC free article] [PubMed]
  • Jenuwein T, Grosschedl R. Complex pattern of immunoglobulin mu gene expression in normal and transgenic mice: nonoverlapping regulatory sequences govern distinct tissue specificities. Genes Dev. 1991 Jun;5(6):932–943. [PubMed]
  • Kadesch T, Zervos P, Ruezinsky D. Functional analysis of the murine IgH enhancer: evidence for negative control of cell-type specificity. Nucleic Acids Res. 1986 Oct 24;14(20):8209–8221. [PMC free article] [PubMed]
  • Kiledjian M, Su LK, Kadesch T. Identification and characterization of two functional domains within the murine heavy-chain enhancer. Mol Cell Biol. 1988 Jan;8(1):145–152. [PMC free article] [PubMed]
  • Lenardo M, Pierce JW, Baltimore D. Protein-binding sites in Ig gene enhancers determine transcriptional activity and inducibility. Science. 1987 Jun 19;236(4808):1573–1577. [PubMed]
  • Müller MM, Ruppert S, Schaffner W, Matthias P. A cloned octamer transcription factor stimulates transcription from lymphoid-specific promoters in non-B cells. Nature. 1988 Dec 8;336(6199):544–551. [PubMed]
  • Murre C, McCaw PS, Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 1989 Mar 10;56(5):777–783. [PubMed]
  • Murre C, Voronova A, Baltimore D. B-cell- and myocyte-specific E2-box-binding factors contain E12/E47-like subunits. Mol Cell Biol. 1991 Feb;11(2):1156–1160. [PMC free article] [PubMed]
  • Nelsen B, Tian G, Erman B, Gregoire J, Maki R, Graves B, Sen R. Regulation of lymphoid-specific immunoglobulin mu heavy chain gene enhancer by ETS-domain proteins. Science. 1993 Jul 2;261(5117):82–86. [PubMed]
  • Nelson C, Shen LP, Meister A, Fodor E, Rutter WJ. Pan: a transcriptional regulator that binds chymotrypsin, insulin, and AP-4 enhancer motifs. Genes Dev. 1990 Jun;4(6):1035–1043. [PubMed]
  • Park K, Atchison ML. Isolation of a candidate repressor/activator, NF-E1 (YY-1, delta), that binds to the immunoglobulin kappa 3' enhancer and the immunoglobulin heavy-chain mu E1 site. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9804–9808. [PMC free article] [PubMed]
  • Rivera RR, Stuiver MH, Steenbergen R, Murre C. Ets proteins: new factors that regulate immunoglobulin heavy-chain gene expression. Mol Cell Biol. 1993 Nov;13(11):7163–7169. [PMC free article] [PubMed]
  • Roman C, Platero JS, Shuman J, Calame K. Ig/EBP-1: a ubiquitously expressed immunoglobulin enhancer binding protein that is similar to C/EBP and heterodimerizes with C/EBP. Genes Dev. 1990 Aug;4(8):1404–1415. [PubMed]
  • Ruezinsky D, Beckmann H, Kadesch T. Modulation of the IgH enhancer's cell type specificity through a genetic switch. Genes Dev. 1991 Jan;5(1):29–37. [PubMed]
  • Scheidereit C, Cromlish JA, Gerster T, Kawakami K, Balmaceda CG, Currie RA, Roeder RG. A human lymphoid-specific transcription factor that activates immunoglobulin genes is a homoeobox protein. Nature. 1988 Dec 8;336(6199):551–557. [PubMed]
  • Shen L, Lieberman S, Eckhardt LA. The octamer/mu E4 region of the immunoglobulin heavy-chain enhancer mediates gene repression in myeloma x T-lymphoma hybrids. Mol Cell Biol. 1993 Jun;13(6):3530–3540. [PMC free article] [PubMed]
  • Shi Y, Seto E, Chang LS, Shenk T. Transcriptional repression by YY1, a human GLI-Krüppel-related protein, and relief of repression by adenovirus E1A protein. Cell. 1991 Oct 18;67(2):377–388. [PubMed]
  • Simon AM, Burden SJ. An E box mediates activation and repression of the acetylcholine receptor delta-subunit gene during myogenesis. Mol Cell Biol. 1993 Sep;13(9):5133–5140. [PMC free article] [PubMed]
  • Smith DB, Johnson KS. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene. 1988 Jul 15;67(1):31–40. [PubMed]
  • Staudt LM, Lenardo MJ. Immunoglobulin gene transcription. Annu Rev Immunol. 1991;9:373–398. [PubMed]
  • Sturm RA, Das G, Herr W. The ubiquitous octamer-binding protein Oct-1 contains a POU domain with a homeo box subdomain. Genes Dev. 1988 Dec;2(12A):1582–1599. [PubMed]
  • Sun XH, Copeland NG, Jenkins NA, Baltimore D. Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins. Mol Cell Biol. 1991 Nov;11(11):5603–5611. [PMC free article] [PubMed]
  • Vinson CR, LaMarco KL, Johnson PF, Landschulz WH, McKnight SL. In situ detection of sequence-specific DNA binding activity specified by a recombinant bacteriophage. Genes Dev. 1988 Jul;2(7):801–806. [PubMed]
  • Walker MD, Park CW, Rosen A, Aronheim A. A cDNA from a mouse pancreatic beta cell encoding a putative transcription factor of the insulin gene. Nucleic Acids Res. 1990 Mar 11;18(5):1159–1166. [PMC free article] [PubMed]
  • Whelan J, Cordle SR, Henderson E, Weil PA, Stein R. Identification of a pancreatic beta-cell insulin gene transcription factor that binds to and appears to activate cell-type-specific expression: its possible relationship to other cellular factors that bind to a common insulin gene sequence. Mol Cell Biol. 1990 Apr;10(4):1564–1572. [PMC free article] [PubMed]
  • Williams TM, Moolten D, Burlein J, Romano J, Bhaerman R, Godillot A, Mellon M, Rauscher FJ, 3rd, Kant JA. Identification of a zinc finger protein that inhibits IL-2 gene expression. Science. 1991 Dec 20;254(5039):1791–1794. [PubMed]
  • Wilson RB, Kiledjian M, Shen CP, Benezra R, Zwollo P, Dymecki SM, Desiderio SV, Kadesch T. Repression of immunoglobulin enhancers by the helix-loop-helix protein Id: implications for B-lymphoid-cell development. Mol Cell Biol. 1991 Dec;11(12):6185–6191. [PMC free article] [PubMed]
  • Yu H, Porton B, Shen LY, Eckhardt LA. Role of the octamer motif in hybrid cell extinction of immunoglobulin gene expression: extinction is dominant in a two enhancer system. Cell. 1989 Aug 11;58(3):441–448. [PubMed]

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